Numerous transition metal complexes have been used as drugs, especially as anti-cancer agents Cisplatin and bleomycin are two examples of drugs which contain a transition metal (platinum and iron, respectively) and both of these are important chemotherapy agents. These drugs, as well as most other anti-cancer drugs, have as their cellular target DNA. Recently, it has been discovered that a new palladium complex (formed by the cyclometallation of PdCl2 with the chelating organic ligand 2'-(2- methoxyphenyl) 1,10phenanthroline) will, in the presence of an oxidant such as hydrogen peroxide, specifically nick DNA at dG residues. Hydrog peroxide alone or in combination with simple palladium salts does not exhibit this specificity. The palladium complex possesses structural features in common with both the Cisplatin group of drugs and with intercalators. Nevertheless, it has novel features, such as a transition-metal carbon bond. One of the goals of this research will be to see if the Pd-C bond is in any way responsible for the palladium complex's DNA nicking activity. The immediate goal of the project will be to determine the chemistry of DNA strand scission produced by the palladium complex. Chromatographic techniques will be used to isolate the strand cleavage products and UV, NMR and mass spectroscopy to identify the chemical residues released upon DNA nicking. An attempt will be made to grow crystals of the palladium nuclease and DNA oligomers, including the dinucleotide d(CpG) in order to understand exactly how the complex binds to DNA. Binding constants and unwinding angles will also be measured in order to characterize the Pd complex-DNA adduct. Finally, structural modifications will be made to the complex in order to increase its DNA binding and cleavage specificity. The Pd complex seems to bind in or through the DNA major groove. It thus should serve as a platform on which other molecules could be attached. Most DNA binding proteins and enzymes which process DNA (such as restriction enzymes and repressor molecules) bind in the DNA major groove and molecules which mimic these enzymes (based on the structure of the palladium metallocycle) will be prepared. The long range goal of this project is to understand how small molecules bind to DNA in order to design and synthesize new DNA binding drugs and also to mimic the properties of some DNA binding proteins. The ability to make synthetic repressor molecules which would bind to specific genes (including oncogenes) for example, would have widespread use in biotechnology and medicine.